Protein Overexpressed in Metastatic HER2+ Breast Cancers

A new study reveals the mechanism used by breast cancer cells to colonize the brain, which occurs in 40% of patients with human epidermal growth factor receptor 2 positive (HER2+) disease.

HER2+ breast cancers are characterized by fast proliferation, and are more likely to recur and metastasize compared with other subtypes. While there are treatments specifically for HER2+ breast cancer, if it metastasizes, treatment options are diminished.

Typically, cancer cells use various approaches to disguise themselves from the immune system and form tumors in distant organs. For HER2+ breast cancer, the mechanisms behind this are not fully known.

The authors discovered that when the cells metastasize to the brain, they wrap themselves in a mesh of the reelin protein from the brain, according to the study published by Clinical and Experimental Metastasis. This allows the cancer cells to disguise themselves and hide from immune cells.

The disguised cells can create brain tumors that can potentially be fatal.

"More women than ever are surviving breast cancer only to die from breast tumors growing in their brains years after they've been declared cancer-free," said lead researcher Rahul Jandial, MD, PhD. "I wanted to understand why women with HER2-positive breast cancer (around 20% of all breast cancers) have higher rates of brain metastases than women with other breast cancer subtypes and in turn, find their biological Achilles heel to develop new medicines."

In the study, the authors compared tissue samples to mastectomy samples from the same patients after performing brain surgery to examine the expression of proteins in both samples.

The authors discovered that reelin was downregulated in primary breast cancer tissue, while it was significantly higher in HER2+ breast cancer that metastasized to the brain, according to the study. This indicates that reelin expression may be implicated in metastatic disease.

"The cells are essentially able to act as spies that look like citizens," Dr Jandial said. "They release a mesh of protein and escape the brain's natural defense weapons, causing tumors to grow in the brain."

This discovery is a significant step towards creating novel therapies to treat brain cancers, especially metastatic disease, according to the study. Metastases are responsible for a significant proportion of cancer deaths, with patients with brain cancer metastases having a 20% chance of survival.

These findings could lead to novel reelin inhibitors that could prevent cancer cells from evading the immune system and significantly reducing survival.